Systems for the water dispersion of drugs are necessary for intravenous administration of drugs that are not water soluble. Some of these systems use dispersions of hydrophobic liquids in water, also known as emulsions. Emulsions may be generally defined as somewhat uniformly-sized, stable or quasi-stable dispersions of liquid droplets in a second carrier liquid. Emulsions of microscopic size are often divided in the literature into nanoemulsions and microemulsions. Nanoemulsions cover the size range of 50-200 nm, and are kinetically stable systems with long term physical stability (against creaming or sedimentation, flocculation and coalescence). Because nanoemulsion systems are only kinetically but not thermodynamically stable, they must typically be created by energetic methods such as sonication and high pressure homogenization.
Emulsification systems in particular are needed for the administration of the anesthetic propofol (2, 6 diisopropyl phenol), a liquid which in is pure state is practically insoluble in water. Propofol is a well-known drug, which is relatively inexpensive to produce as a pure chemical, and which is presently used extensively in human and veterinary medicine as a general anesthetic agent. Propofol is capable of producing deep anesthesia, which resolves in a comparatively short time after administration of the drug is discontinued.
Presently, pharmaceutical propofol is prepared by dissolving it in soybean oil, then preparing an emulsion of this oil with egg phospholecithin in order to produce a final concentration of about 10% soybean oil in saline, with concentration of propofol standardized to 1% of the total liquid preparation. These emulsions, which have the appearance of milk, have droplet sizes of up to 200 nm and may be referred to as “nanoemulsions.” Such commercial propofol emulsions, despite addition of preservatives, are similar to intravenous lipid nutritional preparations, and are excellent preservative media for viruses or even growth media for bacteria. For this reason, all propofol preparations in the United States are restricted to single-patient-use vials and ampoules, with directions for discarding of penetrated containers within hours after first use.
To be distinguished from nanoemulsions are microemulsions, a type of emulsion with a particularly small droplet size, usually ranging from less than about 5 to 50 nm in diameter. Microemulsions are characteristically optically transparent due to the small light scattering from very small droplets, giving them a visual appearance similar to true solutions. Microemulsions are also typically thermodynamically stable with respect to instability, and they often therefore form spontaneously, if given sufficient time. For present purposes, the most desirable microemulsions assemble spontaneously when certain hydrophobic chemicals and water are mixed by simply stirring the mixture, without the need for vigorous agitation, such as sonication.
In this regard, there is particular need for the development of propofol microemulsions for pharmaceutical intravenous use that are optically clear, enabling the use of light diffraction to detect the presence of potential contamination from foreign elements such as bacteria, which scatter light. Also, there is need for propofol preparations which are not as conducive to growth of bacteria and fungi, as the present oil and phospholecithin preparations are. There is a need for propofol preparations which have a long shelf life, and which are easily sterilized. Finally, there is a need for propofol preparations containing far more than the 1% concentration presently commercially available, for use in larger animals, such as horses. Presently such animals requiring general anesthesia must frequently be transported from the field to an urban anesthesia suit setting for gas anesthesia, a procedure which is difficult and expensive. An inexpensive high concentration propofol preparation which could be taken to the animal in the field might serve the general anesthetic needs of a significant fraction of these animals.
Generally, current commercially available emulsion systems for the intravenous delivery of propofol utilize ordinary opaque nanoemulsions of the oil-in-water type. Recently, however, a general microemulsion system for pharmaceutical delivery of active compounds has been disclosed in U.S. Pat. No. 6,602,511, which generally describes a complex formulation for a microemulsion containing: water and a component for adjusting polarity, a “surfactant film modifier” (e.g. ethanol), a pharmaceutically acceptable oil (most preferably “a triglyceride containing at least 70% of fatty acids having 8-10 carbon atoms”), and a mixture of a hydrophilic and hydrophobic surfactant up to about 15% by weight of the total emulsion. The '511 patent claims that the formulation can be used to emulsify a broad range of active compounds such as a “proton pump inhibitor, calcium channel blocker, beta blocker, anesthetic, steroid, antioxidant, rennin inhibitor, alkaloid, cytostatica, anti-coagulant, lipid regulating agent, anti-depressant, neuroleptic, immunosuppressant, immunomodulator, antibiotic, [and] anti-inflammatory agent”. Unfortunately, the patent discloses the application of its microemulsion formulation to only two active compounds: felodipine and “indeno indole”. The usefulness of the invention as a microemulsion containing an anesthetic such as propofol is not disclosed. In this regard, it is noted that patent states that the invention produces a microemulsion which is “transparent and slightly viscous one phase liquid”, but the patent is silent as to the transparency of the microemulsion after the addition of either felodipine or indeno indole. The present inventors note, however, that in order to adapt the complex formulation of the patent to intravenous use, it would be necessary to add a significant amount of carrier liquid and that doing so would cause a significant degradation in the transparency of the microemulsion. The patent also discloses the need for a two (2) component surfactant system: a hydrophilic and a hydrophobic surfactant, which further adds to the complexity of the formulation. Here, the '511 patent follows the common belief that microemulsions systems are most easily made by use of a “co-surfactant” to decrease droplet interfacial tension. However, the inclusion of a hydrophobic surfactant actually retards the formation of the desired microemulsion in water, and is completely unnecessary if the hydrophobic surfactant is chosen properly.
As a result, what is needed is a simple propofol formulation for the production of high concentrations of propofol in a completely transparent microemulsion that can be used as an intravenously administered anesthetic, and if necessary can be suitably colored in order to identify different concentrations of propofol in different preparations. In addition, there is needed a propofol self-microemulsifiable base composition which uses only a single hydrophillic surfactant, is easy to sterilize, can be stored indefinitely until the anesthetic is needed, after which it can easily be reconstituted by addition of a physiologic saline or similar water-based carrier. The present invention satisfies these needs, among others.